Guanidinosuccinic acid (GSAI), an endogenous metabolite accumulating in renal failure, depolarizes cat spinal motoneurons and induces convulsions in mice that are blocked by N-methyl-D-aspartate (NMDA) receptor antagonists. We studied GSA on glutamate transmission in CA1 pyramidal cells in rat hippocampal slices. The excitatory postsynaptic potentials (EPSP) were recorded extracellularly upon stimulation of the Schaffer collaterals. GSA was applied at 1mM, 500, 250, 125 and 62.5 µM on drug-naive slices. After short application of 1 mM GSA a sudden decrease in response was followed by a 1ong-lasling increase. During 40 minute perfusion of 500 or 250 µM GSA an initial enhancement of amplitude was followed by a decreased response, which then recovered to amplitudes greater than initially. This enhanced response was also long-tasting. Fourty minutes of 125 µM GSA induced a gradual monophasic increase of the response. Co -application of the competitive NMDA receptor antagonist D-APV at 50 µM fully antagonized the effects of 250 µM GSA and 25 µM D•APV those of 125 µM GSA. 25 µM D-APV partially inhibited the effects of 500 and 250 µM GSA by changing the profile to the monophasic form. The patterns were mimicked by the similar application of 12.5 and 25 µM NMDA. We conclude that GSA acts as an NMDA receptor agonist. The increased postsynaptic depolarization and the observed polyspike response may be due to the opening of the NMDA receptor. A decreased membrane resistance then induces the diminished response. The recovery may be AMPA-mediated after desensitization of the NMDA receptors restoring the membrane resistance. The long-term potentiation is probably initiated by the increase in intracellular Ca++ during NMDA receptor opening (chemical long-term potentiation).